A number of hematologic diseases have been shown to result from clonal expansion of an abnormal stem cell. In a few cases, typically associated with macroscopic chromosomal structural abnormalities, individual genes have been implicated. Examples include chronic myelogenous leukemia (CML) and the BCR-Abl fusion gene, and acute promyelocytic leukemia (APL) and the retinoic acid receptor. Detection of a specific genetic abnormality has had significant impact on the diagnosis (CML and APL) and treatment (APL) of these disorders. No specific or consistent genetic abnormality has been detected in the majority of clonal bone marrow disorders, including the myelodysplastic syndrome and the myeloproliferative syndromes other than CML. We are using the technique of representation difference analysis (RDA) to look for changes in the somatic DNA of individuals with clonai bone marrow disorders. Abnormal DNA is collected by isolating peripheral blood or bone marrow mononuclear cells. Unaffected DNA used to drive the kinetic enrichment of the abnormal gene can be obtained from several sources. In rare cases, blood or bone marrow specimens are available both before and after the evolution of the disease. In this case, the earlier specimen can serve as the "driver", or normal, and the latter as the "target", or abnormal. In the case of a mutation associated with homozygous loss of genetic material, this order can be reversed. Most patients will not have pre-evolution samples available. In these cases driver DNA can be obtained from a pool of peripheral blood mononuclear cells from the patient's parents (if available) or from skin obtained from the affected individual by bunch biopsy.